Bacillus Calmette-Guerin polysaccharide nucleic acid (BCG-PSN) is a relatively new generation, bacteria lipopolysaccharide fraction extracted from BCG vaccine. It has a strong immunomodulatory effect with higher efficacy and fewer side effects. To assess the clinical efficacy and safety of BCG-PSN vs the viable BCG vaccine in treatment of multiple warts. One hundred twenty patients with warts were allocated into three groups each containing 40 patients. Each group received intralesionally 0.1 mL of BCG-PSN, BCG vaccine, saline in group A, B, and C, respectively, for a maximum of five sessions, 3 weeks apart. Complete response occurred in 77.5% of group A vs 63.8% in group B. Partial response detected in 7.9% of control group (P < .0001). The distant warts showed 72.5% complete clearance in group A compared to 58.3% in group B (P = .19). Group A showed fewer number of sessions (P = .03) and earlier response than group B (P = .0003). A significant increase in the frequency of adverse effects was found among group B than group A (P < .0001). No recurrence was seen in both groups. BCG-PSN immunotherapy has a higher therapeutic efficacy with almost no serious side effects compared to the BCG vaccine in warts therapy.